What is the role of blood-brain-barrier regional specificity in the nucleus accumbens?

伏隔核中血脑屏障区域特异性的作用是什么？

• 批准号: 10469330
• 负责人: Iris Haleakala Garcia-Pak
• 金额: $ 3.97万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10469330
• 关键词: Acute; Address; Adult; Affect; Aging; All-Trans-Retinol; Alzheimer' s Disease; Area; Basal Ganglia; Behavior; Biological; Blood - brain barrier anatomy; Blood Vessels; Brain; Brain region; Cell Differentiation process; Cell Survival; Cerebellum; Cochlear nucleus; Corpus striatum structure; Development; Developmental Process; Diet; Disease; Dopamine; Dopamine D1 Receptor; Dopamine D2 Receptor; Dopamine Receptor; Drug Addiction; Endothelial Cells; Endothelium; Environment; Equilibrium; Exhibits; Functional disorder; Gene Expression; Gene Expression Profile; Genes; Goals; Health system; Heterogeneity; Hippocampus (Brain); Homeostasis; Hypothalamic structure; Immune system; Individual; Knock-out; Knockout Mice; Knowledge; Lead; Learning; Metabolism; Molecular; Mus; Nervous System Physiology; Neuraxis; Neurons; Nucleus Accumbens; Organ; Pathway interactions; Peripheral; Play; Predisposition; Prevalence; Prevention; Property; Psychological reinforcement; Public Health; RXR; Retinoids; Rewards; Role; Self Administration; Sensory; Severities; Signal Transduction; Source; Specific qualifier value; Specificity; Spinal Cord; Stimulus; Tamoxifen; Testing; Thalamic structure; Time; Tissue-Specific Gene Expression; Tissues; Toxin; Traumatic Brain Injury; Tretinoin; Variant; Ventral Striatum; Vitamin A; Work; addiction; brain endothelial cell; cell type; conditional knockout; dietary; extracellular; interest; learned behavior; nervous system disorder; neural circuit; neuropsychiatric disorder; pleasure; receptor; relating to nervous system; single-cell RNA sequencing; therapeutic target

PROJECT SUMMARY/ABSTRACT The blood-brain barrier (BBB) is a term that describes the unique properties of central nervous system (CNS) blood vessels which allow them to stringently regulate the extracellular environment of the surrounding neural tissue. While it is known that different brain regions are made up of diverse cell types and execute distinct functions, it is unknown if the BBB exhibits varied features in functionally distinct regions to regulate specific neural circuits. Since little is known about heterogeneity of the BBB, this project will address this gap in knowledge and pursue the question of whether regional specializations of the blood-brain barrier may regulate local circuit function and behavior. This will identify if the BBB could be targeted to modulate specific behaviors, including reward and addiction. Single cell RNA sequencing revealed that there is significant inter-regional heterogeneity of the BBB via differential gene expression in endothelial cells (ECs). While the canonical BBB genes that contribute to restrictive barrier properties were expressed in ECs across all brain regions, many genes involved in transport, signaling, and metabolism were found to be enriched in ECs of specific brain regions. For instance, Stra6, a transport regulator of retinoids, is remarkably enriched in the nucleus accumbens shell (sNAc) and the ventral cochlear nucleus (VCN) compared to other areas of the brain. The sNAc is particularly of interest because its function in reward and reinforcement learning implicates the region in drug addiction. Due to the prevalence and severity of addiction, it is urgently important to find new targets for treating this major public health issue by asking if the BBB, via Stra6, plays a role in regulating addiction. The proposed study will address this critical need by determining (1) if the regional specificity of Stra6 at the BBB is necessary for the development or adult function of the sNAc, (2) by what molecular mechanisms Stra6 regulates sNAc function, and (3) if Stra6 is required for learning addiction behavior. This proposal will test the hypothesis that Stra6 concentrates retinoids within the sNAc, thereby dynamically regulating dopamine receptor levels and thus the adult function of the sNAc in both spatial learning and addiction. The importance of Stra6 at the BBB will be tested using conditional, EC-specific Stra6 knockout mice to excise Stra6 during development or in adulthood. These aims will also test whether elevating dietary Vitamin A, the source of retinoids, can increase retinoid levels in the absence of Stra6 and rescue sNAc function. The central goals of this proposal are to gain deeper understanding of the BBB’s contribution to brain function, specify mechanisms of addiction, and assess what factors might increase individual susceptibility to drug addiction.

项目总结/文摘